The progressive loss of the regulation of cellular differentiation by epithelial cells can result in cancer. Retinoic acid and some of its analogs (retinoids) can suppress or reverse the transformation of premalignant cells to the malignant state. These compounds can effect the regression of epithelial papillomas induced by carcinogens in experimental animals and can potently inhibit the tumor promotion activity of phorbol esters. Because retinoic acid damages lysomal membranes, is systemically toxic, and has a poor tissue-distribution pattern, retinoids with a better therapeutic index are needed. We propose to synthesize potentially more effective retinoids for the chemoprevention and treatment of epithelial cancer and, in so doing, provide more information on retinoid structure-activity relationships and retinoid metabolic deactivation. Some of the proposed compounds may not be metabolized and therefore should have longer duration of action in the body. Toxicity problems may be reduced since a lower dose would be required. Others could be less toxic, being prodrugs, or would be targeted to specific body organs. Synthetic modifications will be made in a systematic fashion in three regions of the retinoid skeleton--the Beta-cyclogeranylidene ring, the tetraene side chain, and the polar terminus. The compounds prepared will be tested for their effectiveness in inhibiting the induction of the enzyme ornithine decarboxylase induced by phorbol esters; activity in this assay correlates well with antineoplastic activity. Active compounds will also be tested in an antipapilloma assay. Active compounds will be submitted to the National Cancer Institute for additional testing.